The objective of the proposed research is to develop efficient methods for the total synthesis of a number of natural products which have been shown to possess anticancer activity. The target molecules include elephantopin, catharanthine, and vindoline. Our approach for the synthesis of these molecules is based upon the use of sigmatropic rearrangements and cycloaddition reactions as key steps for the formation of new carbon-carbon bonds. We have already demonstrated the feasibility of utilizing sequential Cope-Claisen rearrangements for the construction of cyclodecadiene systems related to those necessary for the synthesis of elephantopin. We have also shown that 2, 3-disubstituted indoles with the functionality required for elaboration to catharanthine and vindoline may be prepared by Claisen ortho ester rearrangement of indole-3-glycolamides. Finally, we have recently prepared an isoquinucleodine which may serve as a precursor for cathranthine by an alternate strategy. The first specific aim of our continuing research is to complete the total synthesis of elephantopin. It is hoped that this research will provide a basis for evaluating the utility of computerized molecular modeling conformational analysis as a means of predicting the stereochemical outcome of transformations involving medium-sized rings. The second specific aim is to complete the total synthesis of catharanthine and vindoline via our Claisen ortho ester strategy. It is hoped that this research will also contribute to the understanding of the factors responsible for the control of certain sigmatropic rearrangements and cycloaddition reactions. The third specific aim of this research is to devise an extremely efficient method for the synthesis of catharanthine via our isoquinucleodine approach. It is hoped that this research will provide multi-gram quantities of catharanthine which could be coupled with vindoline to afford the dimeric Catharanthus (Vinca) alkaloids.